A UFD1 variant encoding a microprotein modulates UFD1f and IPMK ubiquitination to play pivotal roles in anti-stress responses.

Eukaryotic cells make multiple efforts to cope with internal and external stresses; such mechanisms include metabolic responses and the generation of stress-responsive mRNA isoforms (SR-mRNAisos), such as the classical XBP1s. Here, we identified a mammalian conserved SR-mRNAiso, UFD1s, which encodes a microprotein with anti-stress functions. UFD1s decreased the K63-linked ubiquitination levels of UFD1 full-length protein (UFD1f) via competitive binding to the E3 ubiquitin ligase MARCH7, and therefore regulated the dynamics of protein ubiquitination. Inositol polyphosphate multikinase (IPMK) was identified as the most significantly UFD1s-regulated target in terms of changes in K48- and K11-ubiquitination. UFD1s promoted autophagy and fatty acid oxidation, and IPMK was consistently destabilized. Ufd1s-deficient male mice exhibited metabolic disorders and accelerated NASH progression. Plasmid or circRNA expressing UFD1s alleviated NASH in mice, indicating that UFD1s has therapeutic value. Our findings revealed a mammalian conserved microprotein that plays crucial roles in anti-stress regulation through the modulation of ubiquitination and metabolism.